scholarly journals Zoledronate extends healthspan and survival via the mevalonate pathway in a FOXO-dependent manner

2020 ◽  
Author(s):  
Zhengqi. Chen ◽  
Julia Cordero ◽  
Cathy Slack ◽  
Martin Zeidler ◽  
Ilaria Bellantuono
Keyword(s):  
Mevalonate Pathway ◽  
Great Promise ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Farnesyl Pyrophosphate ◽  
Mechanistic Studies ◽  
Farnesyl Pyrophosphate Synthase ◽  
X Ray ◽  
Beneficial Effects ◽  
Extended Lifespan

ABSTRACTIncreased longevity has not been paralleled by extended healthspan, resulting in more years spent with multiple diseases in older age. As such, interventions to improve healthspan are urgently required. Zoledronate is a nitrogen containing bisphosphonate, which inhibits the farnesyl pyrophosphate synthase (FPPS) enzyme, central to the mevalonate pathway. It is already used clinically to prevent fractures in osteoporotic patients, who have been reported to derive unexpected and unexplained survival benefits. In this study we show that zoledronate has beneficial effects on both lifespan and healthspan using Drosophila as a model. We found that zoledronate extended lifespan, improved climbing activity and reduced intestinal epithelial dysplasia and permeability in aged flies. Mechanistic studies showed that zoledronate conferred resistance to oxidative stress and reduced accumulation of X-ray-induced DNA damage via inhibition of FPPS. Moreover, zoledronate inhibited pAKT in the mTOR pathway and functioned via dFOXO, a molecule associated with increased longevity, downstream of the mevalonate pathway. Taken together, our work indicates that zoledronate, a drug already widely used and dosed only once a year to prevent osteoporosis, modulates important mechanisms of ageing. Its repurposing holds great promise as a treatment to improve healthspan.

scholarly journals Zoledronate extends healthspan and survival via the mevalonate pathway in a FOXO-dependent manner

2021 ◽  
Author(s):  
Zhengqi Chen ◽  
Julia Cordero ◽  
Adel M Alqarni ◽  
Cathy Slack ◽  
Martin P Zeidler ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mevalonate Pathway ◽  
Great Promise ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Farnesyl Pyrophosphate ◽  
Farnesyl Pyrophosphate Synthase ◽  
Extended Lifespan ◽  
Climbing Ability ◽  
Genetically Manipulated

Abstract Over recent decades, increased longevity has not been paralleled by extended healthspan, resulting in more years spent with multiple diseases in older age. As such, interventions to improve healthspan are urgently required. Zoledronate is a nitrogen containing bisphosphonate, which inhibits the farnesyl pyrophosphate synthase (FPPS) enzyme, central to the mevalonate pathway. It is already used clinically to prevent fractures in osteoporotic patients, who have been reported to derive unexpected and unexplained survival benefits. Using Drosophila as a model we determined the effects of Zoledronate on lifespan, parameters of healthspan (climbing ability and intestinal dysplasia) and the ability to confer resistance to oxidative stress using a combination of genetically manipulated Drosophila strains and Western blotting. Our study shows that Zoledronate extended lifespan, improved climbing activity and reduced intestinal epithelial dysplasia and permeability with age. Mechanistic studies showed that Zoledronate conferred resistance to oxidative stress and reduced accumulation of X-ray-induced DNA damage via inhibition of FPPS. Moreover, Zoledronate was associated with inhibition of pAKT in the mTOR pathway downstream of the mevalonate pathway and required dFOXO for its action, both molecules associated with increased longevity. Taken together, our work indicates that Zoledronate, a drug already widely used to prevent osteoporosis and dosed only once a year, modulates important mechanisms of ageing. Its repurposing holds great promise as a treatment to improve healthspan.

scholarly journals DNA Methylation of Farnesyl Pyrophosphate Synthase, Squalene Synthase, and Squalene Epoxidase Gene Promoters and Effect on the Saponin Content of Eleutherococcus Senticosus

Forests ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1053
Author(s):  
Zhuo Wang ◽  
Hongyu Guo ◽  
Yantong Zhang ◽  
Limei Lin ◽  
Minghui Cui ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mevalonate Pathway ◽  
Biological Effects ◽  
Squalene Synthase ◽  
Squalene Epoxidase ◽  
Gene Promoters ◽  
Farnesyl Pyrophosphate ◽  
Farnesyl Pyrophosphate Synthase ◽  
Eleutherococcus Senticosus ◽  
Saponin Content

Eleutherococcus senticosus (Ruper. et Maxim.) Maxim is a traditional Chinese medicine. The saponin components of E. senticosus have several biological effects, including reduction of blood lipids; protection against liver, heart, and vascular disease; and antitumor activity. The DNA methylation of E. senticosus farnesyl pyrophosphate synthase (FPS), squalene synthase (SS), and squalene epoxidase (SE) gene promoters and the mechanism of the influence of these enzymes on saponin synthesis and accumulation in E. senticosus were explored using bisulfite sequencing technology, real-time PCR, the vanillin-concentrated sulfuric acid chromogenic method, and LC-MS. There are 19 DNA methylation sites and 8 methylation types in the FPS gene. The SS gene has nine DNA methylation sites and two DNA methylation types. The SE gene has 16 DNA methylation sites and 7 methylation types. The total saponin content in the high and low DNA methylation groups were 1.07 ± 0.12 and 2.92 ± 0.32 mg/g, respectively. Statistical analysis indicated that the gene expression of the FPS, SS, and SE genes was significantly positively correlated with the saponin content (p < 0.05), and that the methylation ratio was significantly negatively correlated with the saponin content (p < 0.01), while the expression of the SS and SE genes was significantly positively correlated (p < 0.01). A total of 488 metabolites were detected from E. senticosus and 100 different metabolites were screened out by extensive targeted metabolomics. The amount of most metabolites related to the mevalonate pathway was higher in the low DNA methylation group than in the high DNA methylation group. It was demonstrated that there are DNA methylation sites in the promoter regions of the FPS, SS, and SE genes of E. senticosus, and DNA methylation in this region could significantly inhibit synthesis in the mevalonate pathway, thus reducing the content of the final product E. senticosus saponin.

scholarly journals QSAR Models for Nitrogen Containing Monophosphonate and Bisphosphonate Derivatives as Human Farnesyl Pyrophosphate Synthase Inhibitors Based on Monte Carlo Method

Drug Research ◽  
2018 ◽  
Vol 69 (03) ◽  
pp. 159-167 ◽  
Author(s):  
Parvin Kumar ◽  
Ashwani Kumar ◽  
Jayant Sindhu ◽  
Sohan Lal
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Method ◽  
Mevalonate Pathway ◽  
Predictive Ability ◽  
Correlation Technique ◽  
Farnesyl Pyrophosphate ◽  
Farnesyl Pyrophosphate Synthase ◽  
End Point ◽  
Qsar Models ◽  
Human Farnesyl Pyrophosphate Synthase

AbstractHuman farnesyl pyrophosphate synthase (hFPPS) is a well-settled therapeutic target and it is an enzyme of the mevalonate pathway which catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate. QSAR studies by using Monte Carlo method for human farnesyl pyrophosphate synthase inhibitors has been carried out using balance of correlation technique with Index of ideality correlation. For construction of QSAR models, six random splits were prepared from the data of 73 phosphonates and hybrid optimal descriptors procured from graph (HFG) and SMILES based notations were employed. The developed QSAR models have robustness, good fitting ability, generalizability and internal predictive ability. The external predictive ability has been certified by testing various precedents. The values of R2, IIC, Q2 and ∆R2 m for the best model are 0.9304, 0.9614, 0.9061 and 0.0861 respectively. The developed QSAR models met with the specified standards given in OECD guideline and applicability domain. The structural feature promoters for the end point increase and promoters for end point decrease have been extracted. The predicted pIC50 for the new proposed compounds have also been reported.

scholarly journals Crystallization and preliminary neutron diffraction experiment of human farnesyl pyrophosphate synthase complexed with risedronate

2014 ◽  
Vol 70 (4) ◽  
pp. 470-472 ◽  
Author(s):  
Takeshi Yokoyama ◽  
Andreas Ostermann ◽  
Mineyuki Mizuguchi ◽  
Nobuo Niimura ◽  
Tobias E. Schrader ◽  
...  
Keyword(s):  
Neutron Diffraction ◽  
Structural Characteristics ◽  
Water Molecules ◽  
Farnesyl Pyrophosphate ◽  
Neutron Diffraction Experiment ◽  
Neutron Data ◽  
Farnesyl Pyrophosphate Synthase ◽  
X Ray ◽  
Complex Crystals ◽  
Clinical Drug

Nitrogen-containing bisphosphonates (N-BPs), such as risedronate and zoledronate, are currently used as a clinical drug for bone-resorption diseases and are potent inhibitors of farnesyl pyrophosphate synthase (FPPS). X-ray crystallographic analyses of FPPS with N-BPs have revealed that N-BPs bind to FPPS with three magnesium ions and several water molecules. To understand the structural characteristics of N-BPs bound to FPPS, including H atoms and hydration by water, neutron diffraction studies were initiated using BIODIFF at the Heinz Maier-Leibnitz Zentrum (MLZ). FPPS–risedronate complex crystals of approximate dimensions 2.8 × 2.5 × 1.5 mm (∼3.5 mm3) were obtained by repeated macro-seeding. Monochromatic neutron diffraction data were collected to 2.4 Å resolution with 98.4% overall completeness. Here, the first successful neutron data collection from FPPS in complex with N-BPs is reported.

Altered expression of farnesyl pyrophosphate synthase in prostate cancer: evidence for a role of the mevalonate pathway in disease progression?

2012 ◽  
Vol 31 (2) ◽  
pp. 345-350 ◽  
Author(s):  
Tilman Todenhöfer ◽  
Jörg Hennenlotter ◽  
Ursula Kühs ◽  
Valentina Gerber ◽  
Georgios Gakis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Mevalonate Pathway ◽  
Farnesyl Pyrophosphate ◽  
Altered Expression ◽  
Farnesyl Pyrophosphate Synthase

Discovery of potent inhibitor for farnesyl pyrophosphate synthase in the mevalonate pathway

2010 ◽  
Vol 46 (29) ◽  
pp. 5340 ◽  
Author(s):  
Jinbo Gao ◽  
Xiusheng Chu ◽  
Yongge Qiu ◽  
Long Wu ◽  
Yuqin Qiao ◽  
...  
Keyword(s):  
Potent Inhibitor ◽  
Mevalonate Pathway ◽  
Farnesyl Pyrophosphate ◽  
Farnesyl Pyrophosphate Synthase

scholarly journals Overexpression of erg20 gene encoding farnesyl pyrophosphate synthase has contrasting effects on activity of enzymes of the dolichyl and sterol branches of mevalonate pathway in Trichoderma reesei

Gene ◽  
2014 ◽  
Vol 544 (2) ◽  
pp. 114-122 ◽  
Author(s):  
Sebastian Piłsyk ◽  
Urszula Perlińska-Lenart ◽  
Wioletta Górka-Nieć ◽  
Sebastian Graczyk ◽  
Beata Antosiewicz ◽  
...  
Keyword(s):  
Trichoderma Reesei ◽  
Mevalonate Pathway ◽  
Farnesyl Pyrophosphate ◽  
Gene Encoding ◽  
Farnesyl Pyrophosphate Synthase ◽  
Activity Of Enzymes

scholarly journals Lentiviral-Mediated Silencing of Farnesyl Pyrophosphate Synthase through RNA Interference in Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-6
Author(s):  
Jian Yang ◽  
Chen-Ze Zhao ◽  
Bin Chen ◽  
Fei Chen ◽  
Jie Han ◽  
...  
Keyword(s):  
Rna Interference ◽  
Mevalonate Pathway ◽  
Transgenic Animals ◽  
Vital Role ◽  
Farnesyl Pyrophosphate ◽  
Perivitelline Space ◽  
Chain Reaction ◽  
Farnesyl Pyrophosphate Synthase ◽  
Polymerase Chain

Farnesyl pyrophosphate synthase (FPPS) plays a vital role in the mevalonate pathway and has been shown to be involved in hypertrophy and cardiovascular diseases. Lentivirus-mediated RNA interference (RNAi) to knock down a gene of interest has become a promising new tool for the establishment of transgenic animals. The interfering fragment, named pLVT202, was chosen from cardiomyocytes tested in vitro and was microinjected into the perivitelline space of zygotes from C57BL/6J mice via a lentivirus vehicle; 20 were identified as carrying copies of the transgene using the polymerase chain reaction (PCR). Real-time PCR and western blotting analysis showed that FPPS was downregulated in multiple tissues in the transgenic mice. The transgenic mouse model provides a novel means of studying the gene function of FPPS.

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